HDAC9 Polymorphism Alters Blood Gene Expression in Patients with Large Vessel Atherosclerotic Stroke

Abstract

The histone deacetylase 9 (HDAC9) polymorphism rs2107595 is associated with an increased risk for large vessel atherosclerotic stroke (LVAS). In humans, there remains a need to better understand this HDAC9 polymorphism's contribution to large vessel stroke. In this pilot study, we evaluated whether the HDAC9 polymorphism rs2107595 is associated with differences in leukocyte gene expression in patients with LVAS. HDAC9 SNP rs2107595 was genotyped in 155 patients (43 LVAS and 112 vascular risk factor controls). RNA isolated from blood was processed on whole genome microarrays. Gene expression was compared between HDAC9 risk allele-positive and risk allele-negative LVAS patients and controls. Functional analysis identified canonical pathways and molecular functions associated with rs2107595 in LVAS. In HDAC9 SNP rs2107595 risk allele-positive LVAS patients, there were 155 genes differentially expressed compared to risk allele-negative patients (fold change > |1.2|, p < 0.05). The 155 genes separated the risk allele-positive and risk allele-negative LVAS patients on a principal component analysis. Pathways associated with HDAC9 risk allele-positive status involved IL-6 signaling, cholesterol efflux, and platelet aggregation. These preliminary data suggest an association with the HDAC9 rs2107595 risk allele and peripheral immune, lipid, and clotting systems in LVAS. Further study is required to evaluate whether these differences are related to large vessel atherosclerosis and stroke risk.

Targeting epigenetics and non-coding RNAs in atherosclerosis: from mechanisms to therapeutics

“…Recent genome-wide association studies have identified several genetic variants of HDAC9 associated with carotid intima-media thickness, peripheral arterial disease, CAD, and ischemic stroke of large vessel (Hacke & Grond-Ginsbach, 2012;Malik, et al, 2017;H. S. Markus, et al, 2013;Matsukura, et al, 2015;Shroff, et al, 2018;. By immunohistochemical staining, HDAC9 was mainly expressed in VSMCs and endothelial cells of cerebral and systemic arteries.…”

Associations among Genetic Variants and Intracranial Aneurysm in a Chinese Population

“…A recent study found that there were significantly gene expression differences between HDAC9 risk allele-positive and negative large vessel atherosclerotic stroke patients, which illustrated that HDAC9 variants may be associated with peripheral immune, lipid, and clotting systems. 35 Whether HDAC9 variants affect IA in a similar manner with that in large vessel atherosclerotic stroke is still unknown. Exact mechanisms should be studied in the future.…”

Smoking affects gene expression in blood of patients with ischemic stroke

“…The criteria for determining significantly differentially expressed genes were P < 0.01 and |fold change| ≥ 1.2. A fold change of 1.2 was used as in our previous studies to help ensure biologically significant changes and to provide enough genes for functional pathway analysis …”